Terpenes and Terpenoids - The Entourage Effect

Terpenes and terpenoids are a large and diverse class of compounds which provide the organoleptic properties (i.e., sensory characteristics like fragrance, flavor) to a wide variety of flowers, fruits, spices and other plants in nature, including Cannabis. The aroma and flavor of Cannabis, and any plant for that matter, is largely a function of its essential oils.

Terpenes and terpenoids are the predominant constituents of these essential oils.

Terpenes and terpenoids are responsible for the diesel piney flavor of some Cannabis varieties, as well as the tropical fruitiness of others. Tens of thousands of these compounds exist in nature. It has been argued that the true purpose of terpenes and terpenoids is to protect the plant from damage due to micro-organisms, insects and animals, and to act as a draw for pollinators.1

Terpenoids are chemically similar to terpenes, but they contain atoms other than carbon and hydrogen, most often oxygen. The two terms are often used interchangeably, however. Terpenes and terpenoids are demonstrated phytotherapeutic agents and are commonly added to foods, beverages and dietary supplements to enhance their palatability and functionality.2

Interestingly, terpenes and phyto-cannabinoids (e.g., THC, CBD, etc.) share the same parent molecule (i.e., isopentenyl pyrophosphate, IPP). If the enzymes from one biochemical pathway get hold of IPP, it will be converted into a phyto-cannabinoid (e.g., THC, CBD, etc.). If the enzymes from a different pathway get there first, it will be converted into a terpene or terpenoid.

The Cannabis plant could theoretically contain hundreds of different terpenes and terpenoids, depending on the genetics and growing conditions.

In reality, the average Cannabis plant may contain around 20 to 40 different terpenes or terpenoids at levels detectable by modern technologies.2

Sativas, Indicas and Hybrids Terpenes and terpenoids are often viewed as key constituents that differentiate Sativa varieties of Cannabis from Indica varieties and from Hybrids. And, as differentiators of individual cultivars (i.e., “strains”) from one another. For example, “Granddaddy Purple”, “OG Kush” and “Lemon Skunk” have different terpene and terpenoid profiles (They also have different phyto-cannabinoid profiles).

If the old adage is correct, that Sativas “give you energy” and “are good to use during the day” and Indicas “act as a sedative” and “are good for pain” and “good to use at night” – then these effects may be mediated by the terpenes and terpenoids in the plant.

Unfortunately, these cultural narratives of Indicas and Sativas are not supported by scientific evidence - at least not yet.

Cannabis flower and products that are labeled as Sativa do not have a consistent and distinct terpene and terpenoid profile as compared to those labeled as Indica, so how could these compounds be responsible for distinct effects in the body?

While terpenes and terpenoids do possess biological activity, a large gap exists between science and culture when it comes to the Entourage Effect.

Fortunately, terpenes and terpenoids found in Cannabis are the subject of current scientific investigations, many of which are designed to better understand their interactions with the endocannabinoid system and their contribution to the Entourage Effect. The Entourage Effect In popular culture, and in scientific literature, the Entourage Effect has become the preferred phrase for describing the synergies created by various constituents within the Cannabis plant. This phenomenon may explain how an extract containing THC and CBD, and other phyto-cannabinoids, as well as terpenes and terpenoids, may be therapeutically superior to isolated THC or CBD. Advocates contend that lower doses of phyto-cannabinoids in broad-spectrum extracts, particularly CBD, are therapeutically comparable to higher doses of isolated phyto-cannabinoids, with fewer adverse effects.

It is a commonly held belief that terpenes and terpenoids contribute materially to the Entourage Effect via phyto-cannabinoid/terpenoid interactions.2

For example, terpenes may increase the permeability of THC thru the blood-brain barrier by altering THC pharmacokinetics.3 Terpenes and terpenoids may also modulate the affinity of phyto-cannabinoids at cannabinoid receptors - in the case of beta-caryophyllene - thru direct interactions with the CB2 receptor.4,5

Despite their history of demonstrated therapeutic effects, terpenes and terpenoids in Cannabis are rarely measured and reported in experimental studies. Furthermore, given the volatility (i.e., tendency to evaporate at normal temperatures) of these compounds, they are often lost during the drying and extraction process, especially the smaller mono and sesquiterpenes. Consequently, they are often absent from many extracts.6 An investigation into terpene loss during the drying process has demonstrated up to a 50% loss over 12 weeks.7 Given these factors, establishing their foundational role in the Entourage Effect is difficult. Their role is often presumed.

The Entourage Effect Debunked? Recent research has not been supportive of the role of terpenes and terpenoids in mediating the Entourage Effect.

For example, a study published in 2018 assessed the impact of terpenes and terpenoids in a full-spectrum extract in a preclinical model of breast cancer.8 The authors concluded that while a full-spectrum extract containing mostly THC was more effective than pure THC, in producing anti-tumor responses in both cell culture and animal models of breast cancer, the enhanced effect was not due to the presence of the five most abundant terpenes in the extract. Studies published in 2019-9 and 2020-10 found that with the possible exception of beta-caryophyllene (a sesquiterpene), which demonstrated a weak interaction with CB2, no data supported the notion that any of the terpenes had direct interactions with either cannabinoid receptor (i.e., CB1 or CB2), nor did they modulate the effects of THC or CBD at those receptors.

This does not mean that terpenes and terpenoids don’t contribute to the Entourage Effect, but it appears that if they do, it is not via cannabinoid receptors.

Conclusion Terpenes and terpenoids are an important class of compounds that comprise the “essential oils” of Cannabis. While they possess their own biological activity, which is independent of phyto-cannabinoids, they are mostly thought of as differentiators of Indica and Sativa varieties, as well as mediators of the Entourage Effect, albeit probably not via cannabinoid receptors.

A large gap exists between science and culture when it comes to these concepts. Fortunately, terpenes and terpenoids found in Cannabis are the subject of current scientific investigations, many of which are designed to better understand their interactions with the endocannabinoid system and their contribution to the Entourage Effect.

References 1. Singh B, Sharma RA. Plant terpenes: defense responses, phylogenetic analysis, regulation and clinical applications2015;No. 2:129-151. Located at: 3 Biotech. 2. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-1364. 3. Frontiers | Cannabis sativa: The Plant of the Thousand and One Molecules | Plant Science. 2018. 4. John M. McPartland D, MS, Ethan B. Russo M. Cannabis and Cannabis Extracts. https://doiorg/101300/J175v01n03_08. 2008. 5. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(26):9099-9104. 6. Sexton M, Shelton K, Haley P, West M. Evaluation of Cannabinoid and Terpenoid Content: Cannabis Flower Compared to Supercritical CO2 Concentrate. Planta medica. 2018;84(4):234-241. 7. Ross SA, ElSohly MA. The volatile oil composition of fresh and air-dried buds of Cannabis sativa. J Nat Prod. 1996;59(1):49-51. 8. Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, et al. Appraising the "entourage effect": Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem Pharmacol. 2018;157:285-293. 9. SantiagoMarina, SachdevShivani, C. A, S. M, ConnorMark. Absence of Entourage: Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Functional Activity of Δ9-THC at Human CB1 and CB2 Receptors. https://homeliebertpubcom/can. 2019. 10. DB F, KJ S, M N, C J, M G. Terpenoids From Cannabis Do Not Mediate an Entourage Effect by Acting at Cannabinoid Receptors. Frontiers in pharmacology. 2020;11.